More than 400 million people are chronically infected with HBV, a small, circular, partially double-stranded DNA virus of approximately 3200 base pairs. Chronic infection can result in cirrhosis (scarring) of the liver, liver cancer, liver failure, and death. Current treatment options for chronically infected HBV patients include interferon, peginterferon, and antiviral drugs, such as lamivudine, adefovir, entecavir, telbivudine, and tenofovir targeted against the polymerase (Pol) region of HBV.
The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full-length strand is linked to the viral DNA polymerase. The genome is 3020-3320 nucleotides long (for the full-length strand) and 1700-2800 nucleotides long (for the short length-strand). The negative-sense, (non-coding), is complementary to the viral mRNA. The viral DNA is found in the nucleus soon after infection of the cell. The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (−) sense strand and a short sequence of RNA from the (+) sense strand. Non-coding bases are removed from the ends of the (−) sense strand and the ends are rejoined. There are four known genes encoded by the genome, called C, X, P, and S. The core protein is coded for by gene C (HBcAg), and its start codon is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced. HBeAg is produced by proteolytic processing of the pre-core protein. The DNA polymerase is encoded by gene P (Pol). Gene S is the gene that codes for the surface antigen (HBsAg). The HBsAg gene is one long open reading frame but contains three in frame start (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1+pre-S2+S, pre-S2+S, or S) are produced. Because of the small size of the genome, many of the open reading frames overlap. For example the S open reading frame overlaps with the Pol open reading frame, specifically, HBV nucleotide positions 155 to 832, coding 226 amino acids of the surface antigen, overlaps with the RT region, nucleotide positions 130 to 1161, of the Pol gene. Drug resistance is associate with mutations in the RT region.
The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into nine genotypes (A-I) according to overall nucleotide sequence variation of the genome. The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and vaccination. Genotypes differ by at least 8% of their sequence and were first reported in 1988 when six were initially described (A-F). Norder H, Courouce A M, Magnius L O (1994). “Complete genomes, phylogenic relatedness and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.” Virology 198 (2): 489-503 (incorporated herein by reference for the description of HBV genotypes). Three further types have since been described (G, H, and I). Shibayama T, Masuda G, Ajisawa A, Hiruma K, Tsuda F, Nishizawa T, Takahashi M, Okamoto H (May 2005). “Characterization of seven genotypes (A to E, G and H) of hepatitis B virus recovered from Japanese patients infected with human immunodeficiency virus type 1.” Journal of Medical Virology 76 (1): 24-32 (incorporated herein by reference for the description of HBV genotypes). “A complex hepatitis B virus (X/C) recombinant is common in Long An county, Guangxi and may have originated in southern China.” Journal of General Virology (2011), 92, 402-411 Journal of General Virology (2011), 92, 402-411. Most genotypes are now divided into subgenotypes with distinct properties. Schaefer S (January 2007). “Hepatitis B virus taxonomy and hepatitis B virus genotypes.” World Journal of Gastroenterology: WJG 13 (1): 14-21 (incorporated herein by reference for the description of HBV genotypes).
HBV has a high degree of genetic variation with nine known genotypes (A-I). Different mutations in the various HBV genotypes are associated with how the virus can escape the immune system or become resistant to antiviral drugs. Ray, K, “Hepatitis: Genetic variability in HBV resistance.” Nature Reviews Gastroenterology and Hepatology 8, 535 (October 2011) (incorporated herein by reference for the description of HBV mutations associated with immune system/vaccine escape and drug resistance).